Cystic fibrosis (CF) is characterized by chronic bacterial airway infection with progressive destruction which contributes to 95% of the mortality from this disease. Disruption of the cystic fibrosis transmembrane conductance regulator chloride channels due to genetic mutations in subjects with CF results in altered fluid and electrolyte transport across the airway epithelium leading to impaired mucociliary clearance which leads to chronic airway infection. Both the acute and chronic aspects of the airway diseased are treated with antibiotics and therapies aimed at optimizing mucociliary clearance. The estimated median survival of CF patients remains low, at 36.8 years. Thus, the need for more effective novel therapies is urgent. Human airways are lined by a thin layer of liquid, airway surface liquid (ASL) that contains many antibacterial peptides which play an important role in innate immunity. The antibacterial activity of ASL is NaCI (salt) sensitive. Lowering the salt concentration in ASL, raises its antimicrobial activity and provide a novel mechanism to prevent airway infection. Xylitol, a 5-carbon sugar, can lower ASL salt concentration without providing a carbon-source for bacteria. Xylitol has been shown to prevent progression of dental caries, and decrease the incidence of acute otitis media. These studies raise an intriguing possibility: inhaled xylitol could enhance airway antibacterial defenses, resulting in a decrease in airway colonization and exacerbations. In our phase 1 safety studies, healthy volunteers and stable subjects with CF tolerated single doses of iso-osmolar and hypertonic xylitol well. In a 2 week, 2 animal species study done under good laboratory practices, beagle dogs and rats tolerated inhaled xylitol well. In this application, we propose phase II trials to test the safety and efficacy of inhaled xylitol in subjects with CF. In an ancillary study, we will evaluate the effect of inhaled xylitol on airway colonization and inflammation in pig CF model that we developed recently. If these studies are successful, inhaled xylitol promises to be a cheap and effective intervention for several conditions in addition to CF, such as non-CF bronchiectasis, chronic bronchitis and ventilator associated pneumonia. RELEVANCE: Cystic fibrosis is the most common genetic lung disease in Caucasians. Recurrent airway infection contribute to 95% of death and short lifespan from this disease. This project is looking to test the effectiveness of a new agent called xylitol that has the potential to decrease bacterial growth in the lungs. Giving xylitol as a nebulizer into the lungs may be a simple and safe way to ward off lung infections. (End of Abstract)